Strokes and other events associated with reductions in blood flow to the brain continue to result in serious and costly neurological sequelae such as: 1) loss of normal neurological function such as movement or memory; 2) altered neurological function (i.e., seizure type activity); and/or 3) death of the affected individual. Examples of disruptions in the cerebral blood flow include, but are not limited to, cardiac failure, hypotensive shock, occlusion of carotid arteries for endarterectomy, occlusion of cerebral arteries for aneurysm surgery, and lodging of microvascular emboli during cardiopulmonary bypass. Further, such events account for considerable costs to society in terms of the medical care and loss of productivity.
A number of putative neuroprotective agents have been developed over the last several decades, but the results of these agents in clinical trials and practice have been disappointing at best. For example, non-selective stimulators of potassium channels such as aprikalim and NS1619 have been shown to protect the brain under a wide range of ischemic conditions. However, two basic limitations typically occur with these compounds. First, these potassium channel stimulators are not selective for cellular localization, so that it is impossible to determine the situs of their function. This is important because the effects of these agents at locations distinct from mitochondria may counteract or interfere with protective functions. Second, mechanisms of action for these non-selective stimulators have yet to be determined, and thus results have been difficult to interpret. There, thus, remains a need to develop neuroprotective agents that can improve neuronal cell function and recovery and prevent cell death after stroke-like events or events associated with reductions of cerebral blood flow (ischemia).